small molecules

2026-07-28 | Depression in Opioid Use Disorder: A Tripartite Psychopathological Model for Dual Disorders.

Depressive symptoms are highly prevalent among individuals with substance use disorders, particularly opioid use disorder (OUD), yet their clinical meaning is often difficult to determine. In routine practice, these symptoms are commonly interpreted within a binary framework, either as manifestations of an independent mood disorder or as substance-induced states related to intoxication, withdrawal, or early abstinence. Although clinically useful, this distinction may not fully capture a third configuration in which depressive psychopathology emerges within the chronic addictive process itself. This Perspective proposes a tripartite model of depressive states in OUD informed primarily by clinical and dimensional studies conducted in populations with heroin use disorder. First, substance-induced depression refers to mood symptoms temporally linked to the acute or subacute pharmacological effects of substances and generally expected to improve with stabilization or sustained abstinence. Second, an independent mood disorder may coexist with OUD, with particular attention warranted for bipolar-spectrum presentations characterized by affective instability, cyclothymic or irritable temperaments, mixed features, and mood-related patterns of substance use. Third, addiction-related depression describes a persistent depressive configuration associated with reward dysregulation, hypophoria, motivational depletion, cognitive inefficiency, and the Worthlessness/Being Trapped dimension identified primarily in dimensional studies of heroin use disorder. These configurations should not be regarded as rigid or mutually exclusive categories, but as longitudinal clinical formulations that may predominate at different stages of the addictive trajectory. Distinguishing among them may improve diagnostic clarity and support a hierarchical clinical approach in which stabilization of OUD is generally an initial therapeutic priority, while antidepressant and mood-stabilizing interventions are guided by symptom severity, temporal course, psychopathological organization, and evidence of an independent mood disorder.

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2026-06-26 | Postmortem Oxycodone Toxicology: A Systematic Review and Meta-Analysis of Concentrations and Interpretative Markers.

Background: Oxycodone is a widely prescribed semi-synthetic opioid central to pain management. However, establishing its role in death when detected in postmortem toxicology is challenging. Quantitative evidence to support forensic interpretation remains limited. Methods: A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines. PubMed and Scopus were searched through 3 March 2026, for studies reporting quantitative postmortem oxycodone concentrations in human biological matrices. Peripheral blood was predefined as the primary matrix for quantitative synthesis. Random-effects meta-analysis with restricted maximum likelihood estimation was performed on logarithmically transformed concentrations to compare fatal intoxications versus non-intoxication deaths and mono- versus mixed-intoxication cases. Pooled estimates were reported as geometric mean concentrations with 95% confidence and prediction intervals. Secondary analyses evaluated metabolite-to-parent ratios, alternative matrices, and postmortem interval (PMI). Results: Twenty-three studies comprising 4335 oxycodone-positive decedents were included in the qualitative synthesis, and 14 studies in the quantitative meta-analysis. Fatal intoxication cases (n = 1555) showed a pooled geometric mean peripheral blood oxycodone concentration of 0.37 mg/L (95% CI: 0.24-0.58; I2 = 93.5%), compared with 0.08 mg/L (95% CI: 0.04-0.15; I2 = 98.5%) in non-intoxication deaths (n = 1409). Mono-intoxication cases (n = 135) exhibited higher concentrations (0.52 mg/L; 95% CI: 0.22-1.21; I2 = 82.3%) than mixed-drug fatalities (n = 511; 0.29 mg/L; 95% CI: 0.13-0.65; I2 = 93.1%). Metabolite data indicated that noroxycodone and oxymorphone patterns may assist in distinguishing acute intake and metabolic variability. Alternative matrices, particularly vitreous humor and solid tissues provided complementary interpretative information, while PMI contributed concentration variability. Conclusions: The key quantitative findings of this meta-analysis indicate higher peripheral blood oxycodone levels in fatal intoxications than in non-intoxication deaths. However, substantial heterogeneity precludes the definition of absolute concentration cut-offs, emphasizing the need to approach postmortem oxycodone interpretation within a probabilistic forensic framework integrating circumstantial evidence, sampling time, metabolite ratios, and data from alternative biological matrices.

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2026-06-01 | Selective opioid-sparing effects of cannabidiol on opioid analgesia in rats.

Cannabidiol, a major non-intoxicating constituent of cannabis, has generated interest as a novel therapeutic for managing several pathological conditions including chronic pain and opioid use disorder. Here, we evaluated the effects of cannabidiol (3.2 or 10.0 mg/kg) on the antinociceptive and the reward-related effects of the opioid analgesic oxycodone (0.56 mg/kg) in rats (male and female Sprague-Dawley) using an operant facial pain assay, locomotor activity monitoring, and the conditioned place preference paradigm. Cannabidiol enhanced the antinociceptive effect of oxycodone without affecting oxycodone-induced rearing behavior, or the acquisition and expression of oxycodone conditioned place preference under the conditions tested. Together, these findings suggest that cannabidiol potentiates the analgesic effects of oxycodone without affecting its reward-related properties. These results support the potential of cannabidiol as an adjunctive, opioid-sparing agent in pain management. PERSPECTIVE: Opioids remain important for treating moderate to severe pain, but adverse effects and misuse liability limit their use. These preclinical findings suggest cannabidiol may enhance oxycodone antinociception under acute painful conditions, without increasing abuse-relevant effects under the conditions tested, supporting further study as an opioid-sparing adjunct.

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2026-05-05 | Experimental assessment of intravenous lipid emulsion in the management of acute fentanyl poisoning

Fentanyl is a highly potent and lipophilic μ-opioid receptor agonist associated with severe neurorespiratory toxicity and a growing incidence of overdose. Although naloxone remains the standard antidote, its relatively short half-life and exclusively pharmacodynamic mechanism of action may limit its efficacy in intoxications involving highly lipophilic opioids. The aim of this study was to evaluate the therapeutic effects of intravenous lipid emulsion (ILE), administered alone or in combination with naloxone, in a rat model of acute fentanyl toxicity. Thirty adult male Wistar rats were randomly assigned to five groups ( n = 6 per group): vehicle control; fentanyl (0.44 mg/kg, i.p.); fentanyl + naloxone (1.0 mg/kg, i.p.); fentanyl + ILE (20%, 1.5 mL/kg, i.p.); and fentanyl + naloxone + ILE. Survival and clinical manifestations (loss of righting reflex [LORR], catatonia-like behavior, respiratory impairment, and convulsions) were assessed over 120 min. Survival was analyzed using Kaplan–Meier methodology, and nonparametric tests were applied for ordinal outcomes. No statistically significant differences in survival were observed ( p = 0.406). However, combination therapy significantly reduced the incidence of LORR compared to fentanyl alone ( p = 0.0152) and produced the most pronounced improvement in catatonia and respiratory impairment scores ( p < 0.001, Kruskal–Wallis test). In conclusion, combined naloxone and lipid emulsion therapy demonstrated superior attenuation of fentanyl-induced neurobehavioral and respiratory toxicity compared to monotherapy, suggesting complementary pharmacodynamic and pharmacokinetic mechanisms. Further adequately powered studies are warranted.

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2026-05-01 | Ketamine enhancement of dexmedetomidine attenuation of methamphetamine-induced agitation in rats.

Methamphetamine (METH)-induced agitation, a major concern in acute METH intoxication, is currently treated with benzodiazepines. Due to current polysubstance use patterns in METH consumption, this treatment may fatally exacerbate respiratory depression produced by opioid adulterants or intentionally co-administered opioids. We previously showed that the α2-agonist dexmedetomidine (DEX), which does not potentiate opioid-induced respiratory depression in clinical practice, can be safely and effectively co-administered with naloxone to attenuate METH-induced agitation following naloxone reversal in METH-fentanyl co-intoxicated rats. While the unique arousability of DEX-induced sedation is clinically useful, the current study tested the safety and efficacy of DEX and adjunctive ketamine (KET) in producing deeper, less arousable sedation when needed (i.e., for severe agitation or to facilitate an intricate procedure). Fifteen minutes after 1 mg/kg METH administration in male rats (simulating treatment of naloxone-unmasked agitation with a delay), low-dose (0.032 mg/kg) DEX ± (56 mg/kg) KET, high-dose (0.18 mg/kg) DEX, or saline was administered. Key measurements included METH-induced locomotor activity (a rat model of agitation), the rat coma scale (a quantification of arousability), and α2-agonist class side effects. Both high-dose DEX and DEX-KET almost completely attenuated METH-induced locomotor activity for 90 min after administration, but with the combination the sedation was deeper during the most intense METH-induced stimulation, and the α2-agonist side effects were less intense and of shorter duration. These data provide proof-of-concept support for the potential use of DEX-KET in producing deeper sedation in METH-induced agitation.

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cell therapies

2025-09-26 | Examining a Stabilization Center for Patients with Alcohol or Opioid Intoxication Transported by Paramedics: A Cohort Study of an Emergency Department Diversion Model.

Emergency departments (EDs) face growing strain from increased health-seeking behavior. To preserve finite ED resources, a non-medical stabilization center (SC) was implemented in Toronto, Canada as an alternative destination to receive paramedic-transported patients with suspected acute alcohol or opioid intoxication who would otherwise have been taken to an ED. These patients typically require observation and recovery rather than emergency medical intervention. We described the diversion care model, clinical guideline, patient cohort, and its safety. We conducted a retrospective study of paramedic-transported patients to a SC in Toronto, Canada between December 8, 2022, and December 31, 2024. Eligible patients originated from 9-1-1 calls and were transported either directly (from the community to SC) or indirectly (from the community to an ED, then to SC). Descriptive statistics summarized the patient cohort stratified by transport method, and those later transferred from the SC to an ED. A total of 3,744 patients were transported to the SC, of which 3,066 (80.3%) were transported directly, and 738 (19.7%) indirectly. Most patients were male and between the ages of 16 and 49 years. Paramedics performed no medical interventions for 3,557 patients (95.0%), with naloxone administered to only 60 cases (1.6%). A small subgroup of patients were frequent users of the SC, with 3.7% of all patients accounting for 24.6% of all visits. A total of 322 (8.6%) initially transported to the SC were subsequently transferred to an ED, primarily for medical concerns unrelated to intoxication. The SC model demonstrated that select intoxicated patients who were unlikely to require paramedic or ED medical care could be safely managed in a non-medical setting, thereby reducing pressure on EDs. These preliminary findings support the integration of paramedic diversion models as part of a broader strategy to optimize emergency care delivery and reduce ED utilization.

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antibodies

2026-06-01 | Depressant NPS—Synthetic Opioids

Abstract The rise of new synthetic opioids (NSOs), including fentanyl and its analogues, nitazenes, and diverse opioids with other chemical structures, represents a significant public health challenge, characterized by their high analgesic potency, rapid onset, and severe health implications. NSOs have dramatically increased overdose fatalities, particularly in North America, because of their high affinity at μ-opioid receptors and their unpredictable presence in illegal substances. Acute intoxication primarily manifests as severe respiratory depression, but some unique additional adverse effects are also seen with certain NSOs. Management of NSO overdoses remains complex, requiring higher or repeated doses of opioid antagonists such as naloxone and potentially longer-acting alternatives as nalmefene. Chronic NSO use is associated with pronounced health consequences, including tolerance, dependence, cognitive impairments, and immune dysfunction. Effective treatment strategies combine medication-assisted therapies, psychosocial interventions, and emerging treatments like monoclonal antibodies and opioid vaccines.

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